Amphotericin B is a broad spectrum antifungal agent with over half a century of use in the treatment of invasive fungal infections [
Based on the available literature, doubling of SCr during treatment with LAmB occurs in 7.6%-19% of patients who receive doses of 5 mg/kg/day or less [
Though the relationship between LAmB and kidney injury has previously been described, little is known about the course of renal recovery after LAmB-induced nephrotoxicity. The timeframe and likelihood of complete renal recovery are unknown, as is the influence of escalating doses on the probability of nephrotoxicity reversal. Historical data links amphotericin B deoxycholate exposure with permanent kidney injury [
The marked differences in reported renal outcomes throughout the literature along with increased utilization of lipid formulations of amphotericin B, and at higher doses, highlight the need for further investigation of nephrotoxic events after LAmB exposure. The purpose of this study was to characterize the pattern of renal recovery after incident AKI during LAmB and determine potential influencing factors, particularly those related to dose.
This retrospective cohort study included hospitalized adults (>18 years of age) at Mayo Clinic in Rochester, Minnesota, who received intravenous LAmB between January 2008 and March 2015. The study protocol was approved by the Institutional Review Board and the need for informed consent was waived. Patients were identified using an institution-specific antimicrobial administration record and were included if AKI developed during LAmB therapy, at least 24 hours after the index administration. Excluded patients had end-stage renal disease, underwent renal replacement therapy in the seven days prior to the development of nephrotoxicity, or did not consent to have their medical records used for research. In an effort to omit AKI cases primarily due to causes other than LAmB, we also excluded patients who exhibited a rise in SCr exceeding 0.3 mg/dL within 24 hours of the first LAmB dose or who were exposed to intravenous contrast within 48 hours of AKI [
At Mayo Clinic Hospital, Rochester, LAmB is the preferred and default amphotericin B product. There is no specific dosing algorithm or dose escalation protocol in use at the institution. Actual body weight is used for dose calculation except in patients weighing >120 kg or with a BMI >40 kg/m2, where adjusted body weight is used. Salt loading with pre- and post-LAmB dose infusions of 250 mL 0.9% sodium chloride was standard practice as a toxicity-prevention strategy [
Acute kidney injury was defined as an increase of at least 50% in SCr from the pretreatment value and the date of AKI was considered to be day 0 in the analysis. This definition has been used frequently in the previously published literature for amphotericin B and was chosen for consistency [
The primary outcome was complete recovery of kidney injury within the first 30 days after nephrotoxicity. Secondary outcome measures included partial renal recovery, mean extent of GFR recovery, and freedom from renal replacement therapy, if applicable. Patients were followed until complete recovery, death, or discharge, or for 30 days after LAmB-associated nephrotoxicity, whichever occurred first. At the end of follow-up, the time to complete recovery and partial recovery was recorded. The time to any recovery was defined as the time to the first detected partial or complete recovery. If the first detected recovery was a complete recovery, a partial recovery was assumed to have occurred on the same day. Daily SCr values were captured when available. For the multivariable analysis, exposure to nephrotoxins occurring during LAmB therapy was collected, including vancomycin, aminoglycosides, polymyxins, angiotensin converting enzyme inhibitors, nonsteroidal anti-inflammatory agents, calcineurin inhibitors, methotrexate, platinum-based antineoplastics, foscarnet, and cidofovir. Additionally, comorbidities that could compromise an individual’s likelihood of renal recovery were gathered if present, including cardio- or hepatorenal syndrome, septic shock, or hypotension requiring vasopressor support.
Baseline patient characteristics were described with frequencies and percentages for categorical variables and means ± standard deviations (SD) or medians and interquartile ranges (IQR) for continuous data. Time to reversal of nephrotoxicity was described using Kaplan-Meier curves. A multivariable Cox proportional hazard model was used to estimate the effect of cumulative LAmB dose on kidney injury recovery, after adjusting for a prespecified set of covariates including age, concomitant nephrotoxins, and baseline renal function [
A total of 735 unique patients with any exposure to LAmB were screened and 98 included after application of eligibility criteria. The most common reason for exclusion was no nephrotoxicity during LAmB therapy (N = 459; 62% of patients screened) (Figure
Baseline characteristics.
| |
---|---|
| |
| 53 (54) |
| 14 (14) |
| 4 (4) |
| 9 (9) |
| 5 (5) |
| 1 (1) |
| 2 (2) |
| 1 (1) |
| 37 (37) |
| |
Mean (SD) | 0.8 (0.2) |
Median (IQR) | 0.7 (0.6-0.8) |
| |
Mean (SD) | 0.9 (0.3) |
Median (IQR) | 0.8 (0.7-1.0) |
Mean Estimated GFR | 91.6 (21.2) |
Consort diagram: 735 patients who received LAmB at Mayo Clinic between 2008 and 2015 were screened. 637 were excluded, leaving 98 patients available for analysis.
After initiation of treatment with LAmB, the median time to AKI was 3.6 days (IQR 2.3 – 7.5). The majority of AKI cases, 48 (48%), were AKIN stage I with 33 (33%) and 18 (18%) cases of stages II and III AKI, respectively. The average LAmB dose at the time of AKI was 4.6 mg/kg/day, and 92 (94%) patients received a LAmB dose less than 7 mg/kg/day. Thirty (31%) patients received a cumulative dose greater than 5 grams. Eight patients (8%) required renal replacement therapy for management of their kidney injury. Median time to initiation of renal replacement therapy was 4.5 days (range 2-17). Fifty patients (51%) were concomitantly receiving at least one other nephrotoxin at the time of AKI, most often vancomycin (Table
Univariate Cox models.
| | | | | |
---|---|---|---|---|---|
| 56 (14.6) | 0.99 (0.81, 1.20) | 0.88 | 0.88 (0.69, 1.13) | 0.32 |
| |||||
Male, n (%) | 63 (64.3) | 0.92 (0.52, 1.63) | 0.78 | 0.84 (0.41, 1.70) | 0.62 |
Female, n (%) | 35 (35.7) | 1.00 | |||
| |||||
Caucasian, n (%) | 87 (35.7) | 0.70 (0.30, 1.63) | 0.40 | 0.56 (0.22, 1.46) | 0.24 |
Other, n (%) | 11 (11.2) | 1.00 | |||
| 28.5 (7) | 1.03 (0.98, 1.07) | 0.23 | 1.01 (0.96, 1.06) | 0.82 |
| 0.9 (0.3) | 1.10 (0.33, 3.73) | 0.88 | 1.27 (0.27, 6.03) | 0.76 |
| |||||
Yes, n (%) | 8 (8.2) | 0.47 (0.11, 1.94) | 0.30 | 5.48 (0.32, 93.61) | 0.24 |
No, n (%) | 90 (91.8) | 1.00 | |||
| 288.5 (244) | 0.97 (0.85, 1.10) | 0.59 | 0.94 (0.80, 1.03) | 0.43 |
| 2445.2 (3144.1) | 0.87 (0.51, 1.48) | 0.60 | 0.87 (0.46, 1.63) | 0.66 |
| 4985.8 (6659.8) | 0.84 (0.58, 1.21) | 0.36 | 0.81 (0.50, 1.31) | 0.39 |
| |||||
Yes, n (%) | 32 (32.7) | 0.79 (0.19, 3.28) | 0.74 | 1.50 (0.35, 6.48) | 0.59 |
No, n (%) | 66 (67.3) | 1.00 | |||
| 1.36 (0.82, 2.25) | 0.24 | 1.49 (0.81, 2.71) | 0.20 |
In 43 patients (44%), LAmB was discontinued within 24 hours of AKI onset. Fifty patients (51%) had LAmB discontinued beyond 24 hours. There was no statistically significant difference in absolute SCr increase between those where LAmB was stopped within 24 hours and those where the drug was continued (0.1 ±0.1 versus 0.07 ±0.1, p=0.31). There was also no statistically significant difference in the percent (%) SCr increase between those where LAmB was stopped within 24 hours and those where the drug was continued (14.7 ±19.1 versus 10.0 ±14.6, p=0.36). Five patients remained on LAmB for at least 30 days, 3 of whom exhibited no recovery of renal function. We did not find an association between early discontinuation of LAmB (i.e., within 24 hours) and renal recovery (HR 0.9, 95% CI 0.5–1.6, p=0.82). In fact, no association was found between discontinuing LAmB at any time and recovery (HR 1.2, 95% CI 0.6–2.4, p=0.55). In the patients who continued LAmB therapy despite AKI, dose reductions were infrequent, occurring in 15 (27%) patients overall.
Complete recovery of renal function occurred in 32 patients (33%) after a mean ± SD of 9.8 ± 7.8 days since AKI onset (Figure
Kaplan Meier curves depicting complete recovery and at least partial recovery over the course of 30 days from AKI. The dotted lines represent 95% confidence intervals.
There was no statistically significant difference in the rates of complete (unadjusted HR 2.7, 95% CI 0.4–19.7, p=0.33) or partial recovery (unadjusted HR 4.9, 95% CI 0.7–35.8, p=0.12) in patients receiving LAmB doses <7 mg/kg/day compared with those who received >7 mg/kg/day. Additionally, cumulative LAmB dose at any point during therapy, number of concurrent nephrotoxins, baseline renal function, and age did not impact recovery of any type on univariable analysis (Table
Multivariable Cox model.
| | |
---|---|---|
| 0.78 (0.52, 1.17) | 0.23 |
| 0.81 (0.51, 1.27) | 0.35 |
| 1.59 (0.88, 2.87) | 0.12 |
| 1.03 (0.82, 1.29) | 0.82 |
| 1.00 (0.93, 1.09) | 0.91 |
In this retrospective study of 98 individuals with LAmB-associated nephrotoxicity, only 36% of the cohort exhibited complete renal recovery within 30 days. Moreover, approximately half failed to experience SCr recovery to within 25% of their pretreatment value during the follow-up period. Likelihood of renal recovery was not predicted by daily dose at the time of AKI, cumulative LAmB dose at the time of AKI, number of concomitant nephrotoxin exposures during the treatment course, comorbidities, baseline renal function, or age.
Amphotericin B is thought to have several mechanisms by which it precipitates nephrotoxicity, including arteriolar vasoconstriction and direct tubular injury [
Luber and colleagues summarized 178 cases of amphotericin B exposure, of which 8–50% experienced a nephrotoxic event [
Interestingly, in the present study, the dose of LAmB was not correlated with an individual’s likelihood of recovering from his or her nephrotoxic event in our study. This was true for the cumulative LAmB dose prior to AKI, the daily dose at the time of AKI, and LAmB exposure after AKI. Although high rates of nephrotoxicity have been reported in patients who receive a cumulative total dose of 5 grams or more of amphotericin B deoxycholate [
Though 51% of the cohort was exposed to concomitant nephrotoxins in addition to LAmB, we found no association between renal recovery and concomitant nephrotoxin use. It has previously been reported that male sex, higher weight, and concomitant use of cyclosporine, vancomycin, and angiotensin converting enzyme inhibitors are all independently associated with a higher risk of LAmB-associated nephrotoxicity [
Definitions of renal recovery after AKI are evolving and no specific one has been used consistently in the context of LAmB-associated nephrotoxicity [
Our study is not without limitations. First, the issue of prescriber bias is inherent in an analysis of this nature. Physicians may be more predisposed to treat sicker patients with higher doses of LAmB due to a perceived risk of treatment failure. As such, we collected data regarding additional exposures that could indicate a higher severity of illness, such as requirement for vasopressor support, presence of hypoperfusing states such as hepato- or cardiorenal syndrome, and the patients’ location during treatment (i.e., ICU or general ward). These events occurred infrequently and thus were not included in the multivariable modeling, potentially limiting the applicability of these findings to the most critically ill patients. We also captured exposure to nephrotoxic medications commonly used in this population. While unlikely, we cannot rule out that administration of other rarely utilized nephrotoxins may have contributed to study findings. Additionally, adherence to salt loading was not explicitly collected therefore we cannot confirm the magnitude of influence, if any, of this practice on the outcome of renal recovery. The definition of AKI in the current investigation was chosen based on those used in prior studies of LAmB nephrotoxicity in an attempt to enhance generalizability of the data. This lacks the sensitivity of AKIN or other definitions which include urine output as a criterion and may have resulted in an underestimation of the rate of AKI, particularly that which was AKIN stage I. Also, it is possible that full recovery of LAmB-associated nephrotoxicity may take longer than 30 days in some patients and their recovery would not have been captured in this analysis. This time frame was chosen based on widely available follow-up data and adds value to existing literature by providing the first defined length of follow-up, furthering our understanding of the clinical course of LAmB-associated nephrotoxicity.
Despite the limitations mentioned above, this is, to our knowledge, the largest investigation of the reversibility of LAmB-associated nephrotoxicity performed to date. More efforts should be made to describe the course of renal recovery in patients with LAmB-associated AKI and the factors which influence it.
Our data suggests that neither LAmB dose at the time of AKI nor cumulative exposure to LAmB impact the likelihood of renal recovery. Further investigation is needed to confirm these findings when aggressive dosing strategies are utilized. Additional research is also warranted to further characterize the course of recovery after LAmB-associated nephrotoxicity, including the comprehensive spectrum of renal recovery and long-term renal outcomes.
The data used to support the findings of this study are included within the article.
An earlier version of this work has been presented in abstract form at the Society of Critical Care Medicine Annual Congress in 2019.
Authors report no conflicts of interest related to the data reported here.